ADAPTations to low load blood flow restriction exercise versus conventional heavier load resistance exercise in UK military personnel with persistent knee pain: protocol for the ADAPT study, a multi-centre randomized controlled trial

Background Muscle atrophy, muscle weakness and localised pain are commonly reported following musculoskeletal injury (MSKI). To mitigate this risk and prepare individuals to return to sport or physically demanding occupations, resistance training (RT) is considered a vital component of rehabilitation. However, to elicit adaptations in muscle strength, exercise guidelines recommend lifting loads ≥ 70% of an individual’s one repetition maximum (1-RM). Unfortunately, individuals with persistent knee pain are often unable to tolerate such high loads and this may negatively impact the duration and extent of their recovery. Low load blood flow restriction (LL-BFR) is an alternative RT technique that has demonstrated improvements in muscle strength, hypertrophy, and pain in the absence of high mechanical loading. However, the effectiveness of high-frequency LL-BFR in a residential rehabilitation environment remains unclear. This study will compare the efficacy of high frequency LL-BFR to ‘conventional’ heavier load resistance training (HL-RT) on measures of physical function and pain in adults with persistent knee pain. Methods This is a multicentre randomised controlled trial (RCT) of 150 UK service personnel (aged 18–55) admitted for a 3-week residential rehabilitation course with persistent knee pain. Participants will be randomised to receive: a) LL-BFR delivered twice daily at 20% 1-RM or b) HL-RT three-times per week at 70% 1-RM. Outcomes will be recorded at baseline (T1), course discharge (T2) and at three-months following course (T3). The primary outcome will be the lower extremity functional scale (LEFS) at T2. Secondary outcomes will include patient reported perceptions of pain, physical and occupational function and objective measures of muscle strength and neuromuscular performance. Additional biomechanical and physiological mechanisms underpinning both RT interventions will also be investigated as part of a nested mechanistic study. Discussion LL-BFR is a rehabilitation modality that has the potential to induce positive clinical adaptations in the absence of high mechanical loads and therefore could be considered a treatment option for patients suffering significant functional deficits who are unable to tolerate heavy load RT. Consequently, results from this study will have a direct clinical application to healthcare service providers and patients involved in the rehabilitation of physically active adults suffering MSKI. Trial registration ClinicalTrials.org reference number, NCT05719922 Supplementary Information The online version contains supplementary material available at 10.1186/s12891-023-06693-3.


INTRODUCTION
This guide is intended to provide supervising clinicians with direction for the interventions employed in the ADAPT research trial. The intervention guide adheres to standards outlined in the Template for Intervention Description and Replication (TIDieR) and Consensus on Exercise Reporting Template (CERT) which sit as extensions of the Consolidated Standards of Reporting Trials (CONSORT) statements for reporting randomised controlled trials (1,2). The guide is based on the available published evidence and clinical practice guidelines recommendations for the conservative treatment of persistent knee pain (both patellofemoral and tibiofemoral pain).
This intervention guide covers: a. Section 1: Delivery of the resistance training protocol. This will describe the two resistance training protocols for the two intervention arms of the study that is conducted whilst the participant attends the residential rehabilitation course.
b. Section 2: Residential rehabilitation course. This section details the overarching components of the residential rehabilitation courses delivered to participants in both the intervention arms at the regional rehabilitation unit study sites. c. Section 3: Rehabilitation following course. This section provides clinical guidelines for the 12-week individualised exercise programme that is prescribed for participants in both intervention arms to continue with following course.

SECTION 1: DELIVERY OF THE RESISTANCE TRAINING PROTOCOL
Both groups will receive conventional rehabilitation care at their regional unit. The only component of treatment that differs between the two groups is the resistance training (RT) intervention prescribed to the quadriceps-based resistance exercises. Participants will be randomised into one of two resistance training groups. Group 1 will perform twice daily low-load (~20% 1-RM) resistance training with BFR (LL-BFR).
Group 2 will perform 4 sets of 12 repetitions of heavier load (~70% 1RM) resistance training (HL-RT) without blood flow restriction (BFR); aligned with more conventional rehabilitation training methods.
Primary RT methods for the strength development of the quadriceps muscles will consist of two lowerlimb exercises: Unilateral leg press using a leg press machine and unilateral knee extensions using a knee extension machine or ankle weights when clinically indicated (3,4). Resistance exercise order will consist of performing the leg press movement followed by knee extension. Prior to the resistance exercise, each participant will undergo a standardised 5-minute progressive warm-up on a stationary bike (Wattbike Ltd, Nottingham, UK).

Group 1: Low Load with Blood Flow Restriction (LL-BFR)
Participants will be asked to perform 4 sets of each exercise whilst wearing a blood flow restriction cuff on the proximal thigh of their affected limb with a personalised tourniquet pressure (PTP) set at 80% Limb Occlusion Pressure (LOP). PTP will be determined prior to each resistance training session (see below). Exercises will be performed with the following sequence of repetitions; 1 set of 30 reps followed by 3 sets of 15 reps (75 repetitions in total) at ~20% of 1RM, with an inter-set interval of 30 seconds, in accordance with previously published protocols (5,6). Between exercises the cuff will be deflated for 3 minutes. A metronome will be set at 60 bpm, with 1s for the concentric phase; no pause; and 1s for the eccentric phase of the lift (1:0:1 tempo) to ensure consistency of lifting between patients.
Training will be performed twice daily, in the morning (between 08:00-11:00) and afternoon (between 14:00-17:00) from Monday to Thursday and once on Friday morning (between 08:00-10:00). Daily RT sessions will always be separated by interludes of at least 5 hours. Over the 15 days of residential rehabilitation, clinical assessments will be carried out on the first day and final two days of the 3-week admission. This allows a maximum of 21 training sessions during the 3-week residential admission.

A.
B.

Determining Personalised Tourniquet Pressure (PTP) for the LL-BFR Group
PTP will be set at 80% of Limb Occlusion Pressure (LOP) in accordance with current available best practice guidelines (7). LOP is defined as the minimum pressure required for full arterial occlusion (7)(8)(9). PTP will be calculated at the start of every session. Prior to exercise, the cuff will be placed on the most proximal portion of the affected lower-limb and PTP calculated with the participant laying semi recumbent in a supine position (hip angle 120°). PTP will be determined using an automatic personalised tourniquet procedure within the system (Delfi Medical, Vancouver, BC, Canada). This procedure is designed to automatically calculate LOP with clinically acceptable accuracy and high reliability (9-11).
The system is comprised of a contour nylon cuff, connected by airtight hose tubing to a personalised tourniquet system (11,12). During the PTP assessment, the device increases cuff pressure in step-bystep increments. To establish LOP the pneumatic pressure pulsations in the cuff bladder are analysed against the arterial pressure pulsations at each cuff pressure increment (12). The PTP will be 80% of the LOP value.
The inflation pressure (80% LOP) will be maintained for the duration of the exercise and then deflated for 3 min to allow the patient to move to the next exercise/equipment station. It will then be re-inflated prior to commencing the second exercise (Knee extension). Thus, the total time under the inflated cuff will be 8 minutes per training session. Our previous protocol paper demonstrated that 8 minutes of BFR training performed twice daily during a busy 3-week admission was both feasible and 100% adhered to by the patient (4).

Group 2: Heavy Load Resistance Training (HL-RT)
Participants will be asked to perform 4 sets of 12 repetitions of each exercise at ~70% of their predicted 1-RM with an inter-set interval of 2 minutes. This sequence of exercise will be repeated 3 times per week, amounting to 9 training sessions during the 3-week residential admission.

Determining Intervention Load
1-RM will be predicted using the 5-RM strength assessment routinely administered across Defence Rehabilitation and detailed as one of the outcome measures for the clinical-based RCT. The use of multiple repetitions (5-RM) lower-limb strength assessments have been shown to accurately predict 1-RM (13,14). The loads lifted (Group 1: 70% 1-RM, Group 2: 20% 1-RM) will be determined using a prediction model commonly used by exercise practitioners (13).

Determining Load Progression and Regression
Assuming patients adapt over the three-week residential programme, the predicted 1RM is expected to increase and therefore we would expect to increase the weight lifted by small increments (e.g. 2.5 kg increases per week). Any increase in weight lifted will be at the discretion of the Exercise Rehabilitation Instructor (ERI), physiotherapist and participant, with training load (the number of repetitions and load lifted) for each session monitored and recorded accordingly. Clinician guidance for load progression/regression: Regression: Exercises should be regressed if the participant (1) cannot complete 80% of total volume, (2) is unable to perform the exercise with correct technique or (3) the participant experiences an increase in injury symptoms either during or within 24 hours following an exercise session. In this case, the exercise load will be reduced. Should unilateral bodyweight movement (without external load) not be feasible, patients will be encouraged to use the other limb to assist. However, the objective will be to progress to unilateral loading as soon as the patient is capable.  (Table 1) will enable daily monitoring of training load, participant wellness scores, symptomatic knee pain and localised muscle discomfort. This will be recorded in a participant booklet/diary that is completed daily by the patient and therapist.

Muscular Discomfort and Symptomatic Knee Pain
A visual analogue scale (VAS) will be used to measure pain intensity. The VAS uses a 100 mm horizontal line anchored by the terms 'no pain' (0) and 'worst possible pain' (100). The VAS response format has shown good internal consistency, is easy to understand, is in wide clinical use, and has been sufficiently evaluated in clinical trial (15). Levels of muscular discomfort and symptomatic knee pain will be recorded immediately prior to starting the exercise, during the exercise and then 5 min post-exercise. Recent studies have demonstrated a hypoalgesia response up to 45 min post BFR training (16). Therefore, all participants will also be asked to score symptomatic knee pain during a pain provoking functional task (single-leg knee bend) immediately prior and 10 minutes following the cessation of exercise. These pain-related outcome measures will be repeated at the start, middle and end of each treatment week to monitor how pain response changes over time to both intervention groups. Muscular discomfort and symptomatic knee pain will be monitored during the 3-week rehabilitation admission using a participant monitoring booklet (table 1).

SECTION 2: REGIONAL REHABILITATION COURSE
The Regional Rehabilitation Unit (RRU) courses include the following key components which are further outlined within the document: a. Assessment and outcome measure collection.
c. Group exercise therapy.
e. Individual exercise programming.

f. Adjuncts to rehabilitation
Timetabling and course capacity will be adapted to suit regional infrastructure constraints such as equipment, staffing, room availability and any social distancing restrictions. The residential rehabilitation course is a semi-structured programme that can be individualised to each patient according to physical assessment findings and response to treatment.
Both groups will attend all sessions within the residential rehabilitation course. The only component of treatment that differs between the two groups is the resistance training intervention prescribed to the quadriceps-based resistance exercises. An individualised course plan should be devised and agreed with the patient. Admission assessment will be recorded within the patient's medical records.

Assessment and Outcome Collection
On-course clinical reviews. To assess progress during the course, one to one patient reviews occur throughout the course (Physio and ERI) either formally or informally. These reviews aim to: a. Ensure that the Individual Programme (IP) has been optimised and progressed / regressed as appropriate for each patient.
b. Monitor symptoms and key subjective / objective markers.
c. To identify early those patients who may require further intervention from the IDT.
d. To ensure that the patient has a clear understanding of their condition e. To refine the patient goals, where required.
Discharge clinic. Prior to departing course all patients will undergo some form of discharge clinic with the Physio and ERI responsible for their care. This will include a course review, finalise IP and agree a rehabilitation plan for the following 3 months. This will be recorded on the patient's medical records. j. Cardiovascular. Short presentation and then practical session providing basic information on heart rate training zones and CV training programmes.

Group Exercise Therapy Sessions
Group exercise therapy session provide a broad overview to introduce the patient safely to the different aspects of rehabilitation. Session format is a short education piece (verbal brief) and then practical session. The clinical staff ensure that suitable exercise progression and regression are catered for.
The following are key components of the group exercise therapy sessions. It is understood these will be adapted to suit regional infrastructure and specific group needs.

Individual Exercise Programme (IP) Sessions
The patient develops their IP throughout the course, which is reviewed and refined during individual programme sessions. Effective and personalised programming of their rehabilitation exercises is discussed during both group-based education sessions and on a one-to-one basis. On discharge the patient will take with them: a. A finalised documented IP.
b. An IP log book that accommodates for their work/family/social commitments.
These are reviewed by clinical staff to ensure patient understanding.

Adjuncts to rehabilitation
Clinicians may utilise adjuncts to rehabilitation to reduce pain in the short term can include the following: manual therapy, taping, foot orthoses. Rehabilitation adjuncts are used as part of a combined intervention approach alongside the patients exercise programme and not used in isolation.
This best represents typical management of persistent knee pain allowing clinicians to select treatment components that address specific impairment identified in individual patients. All adjuncts to rehabilitation to be documented within the participant monitoring booklet.
a. Manual Therapy Manual therapy interventions can be utilised as an adjunct to a patient's rehabilitation programme, however where possible patients should be taught selfmanagement strategies. Manual therapy may include patellofemoral and knee mobilisations and manual soft tissue techniques (e.g. Ischaemic compression to peripatellar, retro patella or myofascial techniques). The addition or removal of techniques is at the discretion of the physiotherapist based upon re-assessment and patient progress.
b. Taping Clinicians may use tailored taping as an adjunct to a patient's rehabilitation programme to assist in pain reduction in the short term.
c. Orthoses Clinicians may prescribe prefabricated foot orthoses for patient with greater than normal pronation to reduce pain in the short term.

Individualized Exercise Programme (IP) Development
Upon course discharge, all participants will be instructed to perform unsupervised exercises outlined in an individualised exercise programme (IP) for a 12-week period prior to their final follow up which will be recorded in an IP log book.
To reflect "real-world" clinical practise, the participant's IP follows a semi-structured format. This is to ensure that the programme is standardized in order to be methodologically reproducible and reportable yet can be individualized dependant on the clinician's clinical findings and participant's rehabilitation goals (17,18). This multimodal IP is based on best practise guidelines from within and outside of UK Defence rehabilitation, and current published evidence in this field. Specific guidance on the choices and constraints for selection and dosage of home exercises is provided.

Individualized Exercise Programme (IP) Parameters
Individualised exercise programme goals: It is out of the scope of the intervention guidelines to advise on cardiovascular fitness and maintenance of non-injured areas. This is completed at the discretion of the treating clinician for the participant to meet British Armed Force Physical Employment Standards.

IP Development and Participant Education:
During the residential rehabilitation course, the study-site clinician will discuss, develop and agree with the participant an individualised exercise programme (IP) to continue for the 12-weeks following course. Whilst on course the participant will be instructed on how to perform the exercises and supervised to ensure correct technique and implementation.
Environment: The IP may be completed at home or within a gym environment. The training location will be documented within the participant's IP log book.
Supervision: After course discharge, the IP will be completed for 12-weeks unsupervised. Whilst on course, the participant will be coached and supervised by a member of the clinical team to ensure correct technique and implementation of the IP.